This RFA is an initiative of the NIH Blueprint for Neuroscience Research (http://neuroscienceblueprint.nih.gov), a trans-NIH partnership to accelerate neuroscience research. Fifteen Institutes and Centers are participating in the Neuroscience Blueprint. This RFA will be administered by the NIMH on behalf of the Neuroscience Blueprint. This funding opportunity supports the design, creation, and characterization of recombinase-expressing C57BL/6 mouse lines to aid in studies of nervous system development and/or function. These so-called “driver lines” should specify expression in distinct cell types and/or other useful temporospatial expression patterns in the nervous system. Drivers with the greatest utility (such as inducibility) and relevance to neuroscience research will be given priority. Applicants should have the capability to create and validate a minimum of 10 novel driver lines in the funding period specified.

The participating Institutes have committed approximately $1.5M to support this RFA in FY06. However, the total amount awarded and the number of awards made will depend upon the number, quality, and cost of the applications received.

It is anticipated that approximately 1-4 awards will be made and that the size and duration of the awards could vary depending on the “throughput capacity” of the awardee(s) and the total number of lines developed. To be considered for funding, applicants should be able to generate and characterize at least ten distinct/novel lines. While the generation of more lines may be a strength of a particular application, the quality and utility of the driver lines will be critical for a favorable review.

This RFA will use a cooperative agreement (U01) mechanism.

Eligible organizations include for-profit or non-profit organizations; public or private institutions, such as universities, colleges, hospitals, and laboratories; units or State and local government; eligible agencies of the Federal government; and, domestic or foreign institutions.

Eligible principal investigators include any individual with the skills, knowledge, and resources necessary to carry out the proposed research. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

Applicants may submit more than one application, provided they are scientifically distinct.

The Neuroscience Blueprint (http://neuroscienceblueprint.nih.gov/) provides a framework to enhance cooperative activities among fifteen NIH Institutes and Centers that support research on the nervous system. By pooling resources and expertise and prospectively coordinating initiatives, the Blueprint can take advantage of economies of scale, confront challenges too large for any single Institute or Center, and develop enabling research tools and resources that will serve the neuroscience community broadly.

The purpose of this RFA is to solicit applications to design, generate, and validate “driver” mouse lines for use in neurobiology research. The use of experimental mice is widely recognized as a critical component in furthering biomedical research, including studies of the development and function of the nervous system. In addition, there are numerous examples of transgenic mouse models for studying various human disorders. Many of the mouse models currently available are strict null mutants, which can have limited utility such as in the case of knockout lethality. Genetic knockouts that are spatially and/or temporally restricted may circumvent lethality or gene compensatory issues and can provide for a more detailed analysis of particular gene products in specified regions or in critical developmental periods or at different ages. Restricted gene expression is generally achieved by crossing a “driver” line (mice containing a recombinase enzyme under the control of promoter elements that specify its expression pattern), with mice containing a “conditional ready” allele that has sequence elements responsive to the recombinase within the gene of interest. A current constraint in neurobiology research is the limited number of useful driver lines for spatial/temporal and/or inducible knockout studies. This initiative will support the construction and validation of cell- and/or regionally-specific driver lines that can be crossed with appropriate “conditional ready” mice to drive predictably patterned gene deletions in order to facilitate neurobiology research. The panel of driver lines created will be a novel and powerful resource that will promote and facilitate additional functional studies. This multi-institute endeavor is coordinated with, and complementary to, ongoing efforts from the NIH Knockout Mouse Project (KOMP) as well as efforts in the European Community to create conditional knockouts. In accordance with Blueprint objectives, it is expected that the driver lines developed and made available to the scientific community through this initiative will cover a variety of different regions within the nervous system with defined expression patterns across the lifespan

The goal of this initiative is to enable the development, generation, and characterization of novel mouse C57BL/6 driver lines to be made available to the broad neuroscience research community and that the data are deposited in the appropriate public database (e.g., dbGSS or Mouse Genome Database, as agreed upon by Steering Committee, that resources developed as part of this project are made publicly available through a repository according to NIH policies, that results are published in a timely manner; and standard nomenclature is used. Relevant data include the genetically-altered mouse lines (in the form of living animals, embryonic stem (ES) cell lines (if ES cells are used), and frozen embryos/spermatozoa), reagents developed for quality control (e.g., PCR primers), vector constructs and details of their design, and documentation of the geno- and phenotype of the mice.

The project will create C57BL/6 (B6) mice, as the demand for this strain is nearly universal in neurobiological studies. Funding is available to support the creation and validation of 50-100 new mouse lines, including the cost of transferring reagents (constructs, ES cells, sperm, embryos, and/or mice) and all relevant data to NIH-funded repositories. Most efforts to date report reduced efficiency of germline transmission using B6 ES cells compared to ES cells from other strains or with chimeras. Recent reports, however, indicate that progress is being made to improve the efficiency of using B6 ES cells and suggest that the “throughput” sought in this initiative is compatible with existing methodologies. However, in recognition of the challenges associated with using B6 ES cells, a parallel RFA (RFA-DA-06-009) will support technology development to improve the efficiency of generating mutant mice using B6 ES cells. Every effort to communicate and coordinate technological advances will be employed among the groups involved.

Applicants to this RFA must propose creative, efficient, and cost-effective methods to generate/characterize a minimum of 10 unique, validated, and novel driver lines per application within five years. The proposed plans must be based on documentable, realistic current capabilities (see additional material for requirements for documentation). Technologies may include, but are not limited to, traditional knockin strategies, BAC transgenics, transposon tagged insertional mutagenesis or other practicable approaches. As the NIH expects to fund more than one award for this effort, applicants should address ways in which the funded efforts can cooperate to ensure that the resource is generated with maximum efficiency while eliminating potential redundancy. The discussion should include the strategy or strategies the applicant will take to generate the constructs, the projected throughput, production goals, the timeline, characteristics of the constructs including reporter genes and inducible elements if applicable, validation by expression profiling, and other quality control measures, and all other pertinent factors. Applicants may propose appropriate collaborations and/or subcontracts for specific elements.

Construct Design: The applicant should provide sufficient details as to how driver constructs will be designed and produced including details/rationale related to the selected recombinase, reporter genes, promoters, and inducible elements if applicable. (Applicants proposing to make inducible lines would be at a distinct advantage.) In addition, the validated source(s) of data used to predict final expression patterns should be discussed for at least several proposed promoter constructs to enable the reviewers to evaluate the criteria/methodology used for selection. These can include (but are not limited to) expression data obtained in the PI’s lab, from published literature, from the GENSAT project, from the Allen Brain Atlas, or other additional sources.

Mouse “driver” generation/validation: The applicant should describe the steps involved in culturing/electroporation (and related) of B6 ES cells. It is recognized that germline transmission in B6 cells is inefficient, but there are several reports of recent successes. The applicant should strive to employ or incorporate the latest techniques and conditions to ensure success using the B6 strain. In addition, the applicant should describe screening procedures and molecular methods to be used to analyze expression characteristics that would address spatial specificity (region, sub-region, cell-type, etc) and/or developmental/temporal/inducible characteristics where applicable (including assessing potential “leakiness” of promoters used).

Archiving vectors/ES cells/embryos/sperm/mice. The applicant should describe in sufficient detail, the methods that will be used to expand and freeze the mutant ES cells (where applicable). This should include compliance with the standards for international repositories, breeding and archiving of validated driver lines and depositing appropriate biomaterials in publicly available NIH-supported repositories or public resource designated by NIH. The applicant should provide information that demonstrates a track record of previous success in completing these tasks on the scale that will be required for this RFA, or the ability to scale to do so.

Data archiving. The applicant should describe all pertinent informatics issues. These should include plans to generate/share vector designs, expression data, and any other relevant information with end users.

Technology development. Incremental technology improvements will play an important role in increasing the efficiency and decreasing the cost of constructing these driver lines. NIH encourages such technology development activities in the applications submitted in response to this RFA. Plans and costs for technology improvement within the project must be well described and justified in terms of leading to a reduction in production costs. The cost of such technology development should be clearly broken out and described so that its contribution to the overall production costs can both be reflected in the per targeting vector or ES cell costs, and be separately identified and evaluated

Crosscutting issues to be explicitly discussed in the application. In addition to the components of the production pipeline outlined above, there are a number of other issues important to the successful operation of a production project that should be discussed separately in the application:

1) Quality control. The applicant should describe measures that will ensure the quality of, or otherwise validate the resources that will be generated, including those mentioned above. The applicant must provide information regarding current and projected success rates for homologous recombination, electroporation and the efficiency of germline transmission using B6 cells. The applicant should address the quantitative aspect of this component (i.e., how many mice need to be made to provide adequate quality assessment) and the costs associated with this effort. Evidence of the effectiveness of such quality assessment programs should be included.

2) Cost per driver line produced: The applicant should describe the cost of generating recombinase-expressing vectors, transgenic ES cell lines, analysis of expression characteristics, and archiving deliverable product(s). The calculated costs must take into account all of the expenses associated with each activity. In addition, the portion of costs that are attributable to informatics infrastructure, quality control, management, and data release should be included in the total cost, but recorded in such a way as to be identifiable. The cost accounting should be done in such a way that the sum of the identifiable cost elements is equal to the unit cost calculated as dollars in/validated mouse line out.

3) Management Plan. The effective management of a production project requires a significant commitment by the Principal Investigator (P.I.). The application should describe the management plan for the proposed project, and how it will support achievement of the proposed goals and milestones. It should describe the organization of the proposed project and its management structure, including integration of the separate components to form an efficient pipeline, key personnel, section leaders, and reporting relationships. Recruitment and training of personnel should be discussed. The plan should describe how the various components of the proposed project will be integrated, and how collaborations or subcontracts, if proposed, will be managed. Additionally, coordination of the project’s activities with other international efforts to produce mouse knockouts should be described.

4) Data and materials release. Applicants should be familiar with the NIH statements regarding sharing of resources developed with Federal funds (http://www.ott.nih.gov/policy/rt_guide_final.html). Responses to this RFA should propose a specific and comprehensive plan for the rapid release of data and materials resulting from this effort to the appropriate databases and repositories, respectively. The quality of this plan will be an important criterion in the review of the application, and the submission of an appropriate plan for release of data and materials will be made a condition of the awards made as a result of this RFA.

In presenting the data release plan, the release of data must be discussed and should include, but is not limited to: (A) details of the construct(s) used for driver gene expression -- information as to the genes that have been assigned to the project, when the effort to create each driver line is scheduled to begin or actually began, when the construct was made, information that the resulting ES cell has been deposited in a public resource designated by NIH and its repository location, information that a mouse embryo has been made, and final confirmation that a transgenic animal has been successfully made and its repository location and expected status (live colony, frozen embryo, sperm, etc) have been determined; (B) for characterization of driver lines -- confirmatory data of transgenic recombinase expression, including spatial and temporal expression patterns.

In presenting the materials release plan, provision for community access should include, but not be limited to: (A) for gene usage -- targeting vectors (sequence and functional properties), mutant ES cells, and transgenic mice, including frozen embryos and sperm samples, derived in the course of the supported work; additionally, applicants should address how software or technology improvements developed under this funding will be publicly released.

The release plans are expected to fully address how the end users of the vectors, ES cells, embryos, mice, and other materials generated by the funded activity, in both the public and private sectors, will be fully enabled to share and use the materials, consistent with achieving the goals of this project. Section IV. 6. “Other Submission Requirements” contains additional sections entitled “Plan for Sharing Research Data” and “Sharing Research Resources.” Only a single plan for the sharing of data and materials is needed and should address information presented in that section as well as the information given in this paragraph.

5) Intellectual Property. The purpose of this initiative is to generate a comprehensive resource of research tools for distribution to the scientific community. The ES cells, embryos, mice, and other resources (“Materials”) generated under this award must be made freely available and accessible for research purposes to the entire research community across the public and private sectors, although it is recognized that different approaches for the two sectors may be appropriate.

Awardees will be free to patent any inventions they develop under this award consistent with the Bayh-Dole Act and NIH policies, but funding of an award will be dependent upon an acceptable plan to ensure that the Materials generated under this award will be available for non-commercial research purposes in a manner consistent with the goals of this funding opportunity.

Investigators responding to this funding opportunity must also address in a plan how applicants will meet the goals of the project by appropriately addressing intellectual property, availability, and accessibility issues known to the Awardee that could materially affect the provision of these research resources from the Awardee to the research community or affect the unencumbered use of the Materials by end-users. Awardees will agree that no reach-through rights to inventions made by end-users of the resources will be permitted under this Award and will not seek reach-through rights to such inventions. To the extent permitted by law, Awardees will grant to the government and the public a non-exclusive, royalty-free license under the patents and other intellectual property rights now owned or controlled by Awardee or developed under this Award to use the Materials for non-commercial research. Without limiting the foregoing, the rights to use Materials, their progeny, and derivatives granted under such license shall extend to breeding of mice whether within a line or with a line of different strain or genetic background.

In addressing these considerations and developing this plan, investigators are advised to confer with their organization’s offices responsible for matters involving technology transfer and sponsored programs, as well as any other relevant offices of their organization.

TECHNICAL ASSISTANCE WORKSHOP

NIH staff will conduct a technical assistance and information-sharing teleconference in Bethesda, MD in December of 2005 or early January of 2006. This teleconference will allow potential applicants to discuss and clarify any issues related to this RFA with NIH staff. If you plan to call in to the teleconference, please contact Dr. Andrea Beckel-Mitchener (e-mail amitchen@mail.nih.gov or phone 301-443-5288) to register to attend and to receive the call-in information. If you are unable to participate in the call, a summary and the questions/responses discussed will be made available on the Neuroscience Blueprint website (http://neuroscienceblueprint.nih.gov) under “Funding Opportunities” soon after the teleconference. Potential applicants are encouraged to submit their questions to Dr. Beckel-Mitchener’s email address listed above in advance of the teleconference. Detailed information about the time of the teleconference will be available on the Neuroscience Blueprint website (http://neuroscienceblueprint.nih.gov) or can be obtained from Dr. Beckel-Mitchener.

6) Non-U.S. applicants. NIH can award grants to international applicants if the application represents a unique approach, resource or service that is not available in the U.S. Non-U.S. applicants should provide a detailed explanation of how their application meets this criterion of uniqueness.

In summary:

Among other considerations and along with any other relevant information discussed in additional sections below, applicants for awards under this RFA:

should discuss the expected throughput and most cost efficient approaches or strategies to be used to make mouse driver lines useful for neurobiology research using C57BL/6 ES cells or alternative method for generating driver strains in a C57BL/6;

should discuss the general approaches or strategies to be used for the production of driver lines/strains including the applicant’s current efforts (throughput and cost) in this area and how those efforts achieve the goals;

should make clear the expected utility and significance of each driver created;

should describe how the project will improve the process of generating mutant ES cells or driver strains of mice with the goal of reducing costs;

should present explicit production milestones and timelines when describing production goals;

should propose appropriate incremental technology development to improve efficiency or inducibility of the gene knockout;

should propose a plan for assessing the quality of the deliverables, including an assessment of the genotoxicity of the recombinase and evaluating spatial/temporal/inducible expression characterization of the resulting mice;

should explicitly discuss project management and how various components of the project will be integrated and how awardees could effectively act in concert as a network;

should propose a comprehensive release plan for the timely release of data and materials so that the resources (including mice) are available to all users;

should propose a comprehensive plan for intellectual property so that the resources and the mice to be made from them are available to all users;

should provide information about the applicant's prior experience in mouse knockout production and available resources;

should discuss interactions, collaborations, or subcontracts that may be appropriate;

non-U.S. applicants should provide information regarding the uniqueness of the resource or approach being proposed and a well documented data and resource release plan.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use thecooperative agreement (U01) award mechanism. Applications are required to be constituted of 3 Research Project Components (as specified under 6. Other Submission Requirements, below) when submitted. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

The NIHU01 is a cooperative agreement award mechanism. In cooperative agreement mechanisms, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".Plans to continue this program beyond the current funding opportunity not definite.

2. Funds Available

The IC(s) of the NIH Neuroscience Blueprint intend to commit approximately $1.5 million dollars in FY 2006 to fund 1 to 4 new grants in response to this RFA. It is expected that individual awards will range between $300 thousand and $1.5 million in direct costs, depending on the number of awards and the size and duration of each. An applicant may request a project period of up to five years and a budget for direct costs up to $1.5 million per year. It is anticipated that awards will be funded in July 2006 for up to five years.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. In addition, partial funding of applications (of a certain individual Research Project or of two particular Research Projects) is conceivable if it were determined through review that the overall effort of the Driver Network (see definitions below) would be strengthened by such an addition.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

For-profit organizations

Non-profit organizations

Public or private institutions, such as universities, colleges, hospitals, and laboratories

Units of State government

Units of local government

Eligible agencies of the Federal government

Foreign Institutions

Domestic Institutions

Awards to Domestic Institutions: Scientists from foreign institutions and NIH Intramural laboratories may participate as collaborators in research projects or scientific cores. Such arrangements may be administered via a subcontract from the grantee institution.

Awards to Foreign Institutions: NIH policy requires that awards directly to a foreign institution be made only for unique resources or scientific contributions to research. Therefore, the applicant must provide justification as to the unique contribution an international site will provide for the application

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs.

Applicants for this RFA must be able to design, generate, and characterize (as described) at least 10 new driver lines during the time of the award. Supporting documentation of this production level (or the potential to achieve it) must be included in the application.

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Charge back of customs and import fees is not allowed.

Format: every effort should be made to comply with the format specifications, which are based upon a standard US paper size of 8.5" x 11."

Prospective applicants are asked to submit a letter of intent that includes the following information:

Descriptive title of proposed research

Name, address, and telephone number of the Principal Investigator

Names of other key personnel

Participating institutions

Number and title of this funding opportunity

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, andthreesigned photocopies in one package to:

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: https://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by program staff at NIMH and other Neuroscience Blueprint Institutes and Centers.Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at https://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement https://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.

An application is expected to be put forward by scientific collaborators focused on research projects that will accomplish the goals of this initiative. It is expected that the participating groups will include outstanding scientists and support staff with relevant scientific expertise and access to suitable facilities. It is anticipated that three main Research Project components will need to be addressed adequately in each application (vector design/construction, generation of the driver mice, and expression verification/characterization of the resulting driver mice). In the applicable sections, the applicant should adequately address technology development as well as data and animal sharing plans. Ultimately, the NIH will support a cooperative Driver Network (see definition below) to generate and validate the driver lines, so it is conceivable that partial funding of applications may result if it is determined that a Research Project component of a U01 could significantly strengthen the overall Driver Network..

1. SPECIFIC INSTRUCTIONS FOR PREPARING THE GENERAL DESCRIPTION

The objectives of the applications submitted should be relevant to and compatible with the goals specified in this RFA. Applicants should describe their plans to accommodate the stated requirements and criteria with specific information items that the reviewers will find to be helpful in assessing applications. The following guidance summarizes the form and format that the applicant must use to provide that information. If there is additional information not addressed in this guidance that the applicant wishes to present, s/he is encouraged to provide it in a concise form, in addition to the information requested here.

The section should precede the individual Research Project components, must not exceed 10 pages, and should provide the following details:

A brief overview of the proposed effort; this overview should describe the proposed contribution of each of the individual Research Projects towards achieving the objectives of the Group. The administrative arrangements and research support should be described. In particular, when more than one institutional site is involved, a detailed description and supporting documentation for the administrative arrangements must be included.

A clear and brief description of how each component Research Project will contribute to the overall objectives, including available professional and technical personnel to permit efficient and successful conduct of the proposed research, and description of the contribution of each to fulfillment of group objectives. The name, organization, and scientific discipline of the Principal Investigator, Research Project Leaders, and other key personnel should be included. A clear description of the interrelationships among the members of the group needs to be made.

A brief description should be provided that summarizes each component Research Project has the available facilities and resources required to attain the expected throughput, including timelines for doing so.

A plan to assure the maintenance of close collaboration and effective communication among members of the group that will include letters of commitment to this plan by all Research Project Leaders where applicable. Include plans for scheduling group meetings, notifying group members (including the NIMH), and documenting and disseminating group meeting proceedings.

The application must make clear how the group (and Research Project Leaders for individual components) will interact in the context of the Driver Network should more than one award be made.

Prior experience in attaining milestones and current capacity (including rapid release of data and materials) relevant to the goals of the application should be described for each component Research Project. The applicant should discuss any experience in defining and meeting useful milestones for a biological production effort.

2. INSTRUCTIONS FOR PREPARING THE RESEARCH PROJECT COMPONENTS

In addition to the details described here for U01 applications, applicants also need to be aware of information described under the “Review and Selection Process” and “Additional Review Criteria” sections below.

Applicants should follow the PHS 398 instructions, including: face page (form page 1); description, performance sites, and key personnel (form page 2); research grant table of contents (appropriate to the application's content); detailed budget of overall application for the initial budget period (form page 4); and budget of overall application for entire proposed period of support (form page 5). This should be followed by an introductory section of no more than ten pages that provides a General Description of the overall effort. The content requirements of this General Description section are described in #1 above.

Following the General Description, each component (the Research Projects) should be presented individually. Each project should have the following: a cover page stating the Project number, the Project title, and Project PI; a form page 2 which includes the description, performance site, and key personnel; individual project budget pages (for the initial budget period and for the entire budget period), followed by the budget justification; biographical sketches; resources; and research plan.

For each Research Project component (Vector design/construction, Generation of driver mice, Verification/characterization of driver mice) there is a 15-page limit for sections a-d of the research plan (i.e., specific aims, background and significance, preliminary studies/progress report, and research design and methods), as indicated in the form PHS 398; there is no page limit for sections e-I, in which Human and Animal Subjects are described . Appendix material limits apply to each component separately, and appendices are limited to the contents specified in the form PHS 398. They should be bundled separately, component by component. Although applicants are allowed 15 pages for each component, it is recognized that sufficient detail might be achieved in less than 15 pages and brevity is appreciated.

For each Research Project component, the research plan needs to address:

The major goals and objectives of the project and their relationship to the overall effort to make novel driver lines for studying the nervous system.

In section(s) a-d as appropriate, the track record and status of current research efforts, the limitations of existing approaches, and how the research questions posed relate to the objectives of the particular project and the overall effort.

The feasibility of the proposed experiments, the advantages of new methodologies (if any), the potential pitfalls, alternative approaches, the means of assessing success of the research to meet the objectives of the individual project and the overall effort.

Specific items to be addressed, likely organized as Research Project components:

A. Vector Design/Construction. The applicant should describe past and current efforts to construct targeting vectors especially those that express recombinases and conditional elements, whether or not they were made using BAC recombineering or other approaches. If other approaches are used, a clear presentation of the methodology must be presented. The discussion should address vector design and construction, generation of probes, and validation steps. The applicant should also describe the throughput rate, quality, and cost, and should include, but not be limited to, the following information:

The number of targeting vectors made in the past year either by BAC recombineering or by other means.

The types and rationale for including specific transgenes, including recombinases, conditional elements, reporters etc.

The generation of probes validating the transgene(s). Was the screening PCR based? Was any sequencing performed to confirm the recombination? Were both 5’ and 3’ insertion points analyzed? What was the monthly success rate of vector and probe generation during the most recent six month period? What were the main reasons for failures? Is there existing capacity to scale up?

Any other metrics that the applicant has found to be useful in evaluating and managing targeting vector and probe production.

B. Generation of C57BL/6 Driver Mice.

If C57BL/6 ES cells are used, the applicant should describe efforts to generate mutant ES cells by gene targeting methods. The numbers successfully produced, as a percentage of attempts should be clearly identified. The discussion must address the steps of electroporation, screening to ensure that integration has occurred, quality control efforts, growth and freezing of the mutant ES cells for storage. The applicant should describe the rate of throughput, quality (e.g., pathogen screening and germline transmission rate), and cost, and should include, but not be limited to, the following:

Throughput rate and quality: the number of targeted ES cells made in the past six months; and/or state clearly how the expected throughput for this RFA would be realized.

Steps taken to ensure that homologous recombination has occurred. What is the copy number of the insert in each mutant? What is the current success rate and how has it changed over the course of the past year?

Procedures for expanding and freezing mutant cells for storage and distribution. Quality control measures to ensure proper freezing and storage conditions.

The steps (including a cost estimate) currently utilized to produce mice from a limited number of ES cells as a quality control measure.

Any other internal metrics that the applicant has found to be useful in evaluating and managing the production of targeted ES cell mutants.

C. Verification/Characterizing of C57BL/6 Driver Mice. The applicant should describe efforts to characterize mice and the techniques used. The applicant should describe the ages and conditions tested including rationale for each, molecular assays and histological analyses used, and include the rate of throughput, quality, and cost.

If methods other than the generation of ES cells (such as highly efficient transposon or gene trap vector systems) are used to create C57BL/6 mice, the applicant must present a clear plan for achieving production of the expected number of driver lines. All phases of the production process should be addressed in sufficient detail, including vector design (component A), construction of mutant mice (component B), validation steps generation of probes, histology etc (component C) to demonstrate that an appropriate and validated line has been made. In addition to clear detailed descriptions of the technology proposed, the applicant should include a General Description as described above and specifically address projected milestones, potential bottlenecks or other problems that may be anticipated, budget details, and all other relevant materials.

Plan for Sharing Research Data

The intent of this initiative is to produce a publicly available resource of novel mice used to drive expression of a useful recombinase in the C57BL/6 genetic background to be used with appropriate “conditional ready” knockouts. As part of this goal, data describing the mutant mice and their production must be available to all users of the resource. The general NIH data sharing policy is available at https://grants.nih.gov/grants/policy/data_sharing. However, this policy is insufficient for this effort, as it does not require sufficiently rapid data release. Thus, all investigators responding to this funding opportunity must include a specific and comprehensive plan for the rapid release of data and resources resulting from the production effort. Section I. “Research Objectives” contains a section entitled “Data and Materials Release” that outlines the issues that must be addressed in a data sharing plan.

The reasonableness of the data sharing plan will be assessed by the reviewers, who will include this assessment in their determination of scientific merit or priority score. In addition, the adequacy of the data sharing plan will be considered by Program staff of the funding organizations when making recommendations about which applications to fund. The effectiveness of the data sharing activities subsequently will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, https://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

The reasonableness of the research materials sharing plan will be assessed by the reviewers, who will include this assessment in their determination of scientific merit or priority score. In addition, the adequacy of the materials sharing plan will be considered by Program staff of the funding organizations when making recommendations about which applications to fund. The effectiveness of the materials sharing subsequently will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, https://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

The following will be considered in making funding decisions:

Scientific merit of the proposed project as determined by peer review

Availability of funds

Relevance of program priorities as a matter of achieving balance in the context of the entire effort as well as attaining the overall goals

The likelihood that the proposed effort will make a significant contribution to the availability of mouse driver lines to the neuroscience research community

The prospect of contributing important methodological advances/improvements to the overall goal of a driver resource with regard to throughput, quality, and cost.

The quality of the plan to share resources and data to make them available to the public and private research community.

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the National Institute of Mental Health in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score.

Receive a written critique.

Receive a second level of review by The National Advisory Mental Health Council or other appropriate national advisory council

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?To what degree does the proposed plan for developing mouse driver lines support the needs of the neuroscience research community? What is the perceived impact of the application in terms of the goals of the RFA?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Are the proposed milestones well reasoned and appropriate? Are the scientific contributions of Research Project components adequate to achieve the goals?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

2.A. Additional Review Criteria:

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, applications received in response to this RFA will also be reviewed with respect to the following:

The likelihood that the proposed project can produce at least 10 validated driver lines based on past experience and future plans for generating these resources including levels of throughput, quality, and cost.

The potential of the research plan to increase throughput while lowering costs.

The quality of the plan for technology development

The quality of the plans for managing bioinformatics (databases, organization/publication of vector design, phenotype data etc), including infrastructure/laboratory information management.

The quality of the plan for the timely sharing and release of resources and data, including evidence that the systems are in place to support data release, and the plans for release or distribution of the resources generated or technologies developed under this award (see sec. 2D Sharing Research Resources below).

The quality of the plans to coordinate with other efforts to generate mouse driver lines in the U.S. and abroad, and with appropriate subcontractors or collaborators that may be needed.

The quality of the plan and ability to work as a coordinated network (the Driver Network) to achieve the goals.

The record of the Principal Investigator and other key personnel in producing transgenic animals.

The reasonableness of the proposed, milestones, timelines, and goals in relation to the proposed research.

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement https://grants.nih.gov/archive/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.The plan should, at a minimum, include how, where and when the biological deliverables (vector constructs, ES cells, mice etc) are to be made available in repositories and how, where, and when the characterization data for the driver lines generated will be placed in the public domain.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 14 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the Principal Investigator for the Group, although specific tasks and activities in carrying out these studies may be shared between the awardees and the NIMH Coordinator(s) as defined above.

The DRIVER NETWORK is defined as the final group of Awardees funded through this effort. This may include one or more whole Research Projects in their entirety as originally submitted and/or may include individual Research Project components chosen to add value to the overall effort. The Project Leaders (Directors of Research Components) and components of the Driver Network will be expected to work in collaboration with each other, the Steering Committee, and the NIH Coordinators to achieve the goals of the initiative.

2.A.1. Principal Investigator Rights and Responsibilities

The P.I. will have the primary authority and responsibility for defining the details for the production effort within the guidelines of this RFA-MH-06-007 and for performing the scientific activities. She/he will assume responsibility and accountability to the applicant organization and to the NIMH for performance and proper conduct of all supported research in accordance with the Terms and Conditions of Award. The P.I. will agree to accept close coordination, cooperation, and participation of NIH staff and advisors in those aspects of scientific and technical management of the project as described under "NIH Program Staff Responsibilities."

Ensure that the products of the production effort meet the quality standards and costs agreed upon at the time of award;

Ensure that the data are deposited in the appropriate public database (e.g., dbGSS or Mouse Genome Database, as agreed upon by Steering Committee, that resources developed as part of this project are made publicly available through a repository according to NIH policies, that results are published in a timely manner; and standard nomenclature is used.

Adhere to the NIH policies regarding intellectual property, data release and other policies that might be established during the course of this activity;

Submit data for quality assessment in any manner specified by the Steering Committee or the NIH Working Group;

Submit periodic progress reports in a standard format, as agreed upon by the Steering Committee;

Accept and implement any other common guidelines and procedures approved by the Steering Committee;

Accept and participate in the Driver Network by contributing cooperatively to the project;

Coordinate and collaborate with other U.S. and international groups producing relevant mouse mutants;

Inform the NIH Program Director of all major interactions with members of the Steering Committee;

Attend Steering Committee meetings;

A Research Project Leader is a senior scientist with proven independent research capabilities who serves as director of one of the scientific Research Project components for the group and is responsible for the scientific conduct of that program. The Principal Investigator may be a Project Leader. Foreign scientists and NIH intramural scientists may be Project Leaders.

Principal Investigators and Research Project Leaders will be expected to attend an annual meeting to review progress and share information among awardees.

NIH intramural scientists involved in the Driver Network will have the same rights and responsibilities as the comparable extramural scientists involved in the Driver Network.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

The NIMH Coordinator will have access to data generated under this cooperative agreement and may periodically review the data consistent with current DHHS, PHS, and NIH policies. Timely publication of major findings by the Group members is encouraged. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NIMH support, including the assigned cooperative agreement award number. The Awardee must submit the INTELLECTUAL PROPERTY AND RESEARCH RESOURCE SHARING PLANS to the NIMH for review to ensure consistency with NIH policy.

2.A.2. NIH Responsibilities

NIH COORDINATORS. During performance of the award, two scientists from the extramural program staff representing the Neuroscience Blueprint will serve as the NIH Coordinator(s), with substantial involvement above and beyond the normal program stewardship role of a Program Official, as described below.

The Primary NIH Coordinator interacts scientifically with the Principal Investigators and Research Project Leaders and, using recommendations from the NIH Working Group, facilitates the role of the NIH Neuroscience Blueprint as a partner in the research. A second NIH scientist will be appointed as an Alternate NIH Coordinator who can attend meetings when the Primary Coordinator is unavailable to ensure adequate NIH representation. The NIH Coordinators will be appointed after award by NIMH in consultation with the NIH Working Group and will have one vote on the Steering Committee even when more than one NIH Coordinator (Primary and Alternate) is designated and present.

It is anticipated that decisions in all activities of the Driver Network will be reached by consensus of the Steering Committee and that NIH staff (through the participation of the NIH Working Group and the NIH Coordinator(s)) will be given the opportunity to offer input to this process. The NIMH Coordinator interacts scientifically with the group and may provide appropriate assistance, including assisting in research planning, recommending spatial/temporal expression targets within the scope of the Driver Network’s objectives and research activities, presenting experimental findings to the group from published sources or from relevant contract projects, participating in the design of experiments agreed to by the group, participating in the analysis of results, and advising in management and technical performance and helping to ensure that duplication is avoided. The NIMH Coordinator(s) will be a voting member(s) of the Steering Committee, and offering a single vote. The NIMH Program Official may attend Steering Committee meetings as a non-voting participant. In all cases, the role of NIMH will be to assist and facilitate and not to direct activities.

The NIH Coordinator(s) will:

Participate (with the other Steering Committee members) in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The NIH Coordinator will assist and facilitate the group process and not direct it;

Negotiate throughput, quality, and cost goals with the awardees of the Driver Network as necessary;

Serve as a liaison between the awardees and the NIH Working Group as well as the larger community in helping the awardee(s) select useful driver targets;

Coordinate the efforts of the Awardees with other participants, including other awardees under this RFA, with other U.S. efforts, with the international community; as well as with the larger biological community;

Attend all Steering Committee meetings as a voting member and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action.

this should be the responsibility of the Chair of the Steering Committee.Periodically report progress to the NIH Working Group and the Directors of the NIH Institutes and Centers supporting this initiative through the Neuroscience Blueprint;

Lend relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve as external scientific advisors on the Steering Committee;

Serve as liaison between the Steering Committee, the Driver Network, and the NIH Working Group;

Serve on subcommittees of the Steering Committee as appropriate;

Provide advice in the management and technical performance of the investigation;

Assist in promoting the availability of the mouse mutants and related resources developed in the course of this project to the scientific community at large;

Participate in data analyses, interpretations, and where warranted, co-authorship of the publication of results of studies conducted through this initiative;

Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;

Retain the option to recommend, with the advice of the NIH Working Group and external scientific advisors, the withholding or reduction of support from any cooperative agreement that substantially fails to achieve its goals according to the milestones agreed to at the time of award, or fails to comply with the Terms and Conditions of the award.

An NIH WORKING GROUP, whose primary role is to ensure that the driver lines generated represent the diverse interests of the participating Blueprint Institutes and Centers, will advise on constructs/mice/activities relevant to their individual Institute/Center mission, monitor overall progress, attend Steering Committee meetings as required, and report back to their Institute/Center. The NIH Working Group will be composed of Program Officials (including the NIH Coordinator(s) from participating Blueprint Institutes and Centers and the NIH Coordinator(s). The NIH Coordinator will chair the NIH Working Group, and communicate their opinions and recommendations to the Steering Committee.

Additionally, an NIMH Program Official will be responsible for the normal scientific and programmatic stewardship and guidance for the overall project within the NIMH and will ensure that the design, generation, and characterization of driver lines are relevant to the diverse research community represented in the Neuroscience Blueprint. The Program Official will be responsible for ensuring that the milestones are being achieved and goals are being met. In addition, the NIMH Program Official is responsible for monitoring and implementing the both the Data Sharing Plan (https://grants.nih.gov/grants/policy/data_sharing/index.htm) and NIH Policy for Sharing Model Organisms (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-066.html). The NIMH Program Official may attend Steering Committee meetings as a non-voting participant. The NIMH Program Official will be named in the award notice. The Program Official also may serve as an NIMH Coordinator for a Group.

2.A.3. Collaborative Responsibilities

DRIVER NETWORK STEERING COMMITTEE. A governing Steering Committee, composed of the P.I.s, Research Project Leaders, Core Directors, NIH Coordinator(s) and external scientific advisors (experts to be named after award) will be established to help monitor progress, encourage improvements, and coordinate the development of the mouse lines/strains through the Driver Network. The Steering Committee members will meet periodically to plan and design activities, review and discuss progress, and establish priorities and Network policies. A chair will be designated from the external scientific advisors (not a PI) on a rotating 1 year basis. Each PI, Project Leader, Core Director, and external scientific advisor will have one vote each and the NIH will have one vote through the participation of the NIH Coordinator(s). The frequency of meetings, not fewer than one per year, will be determined by the Chair who will be responsible for scheduling the time and place and for preparing concise proceedings or minutes (two or three pages) which will be delivered to the Steering Committee members within 30 days of the meeting.

The Steering Committee will:

Discuss progress in meeting the research community's need for mouse driver lines.

Help to develop uniform procedures and policies, for example for data quality measures and assessment, nomenclature and annotation conventions for data depositions, and so forth. Awardee members of the Steering Committee will be required to accept and implement the common guidelines and procedures approved by the Steering Committee.

Serve as a venue for coordination on improving mouse driver production, for example by reporting progress, disseminating best practices and collectively evaluating new procedures, resources, and technologies.

Serve, in appropriate subgroups, as a coordinating body so that projects can collaborate closely on selection and generation of appropriate driver constructs/mice. In these cases, for example, common policies and data exchange will be critical to the success of the effort and will eliminate duplication/overlap.

Each full member will have one vote including the NIH represented by the NIH Coordinator(s) on the Steering Committee. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2.A.4. Arbitration Process

Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIH may be brought to arbitration. An Arbitration Panel will be composed of (i) a designee of the Steering Committee chosen without the NIH staff voting, (ii) one NIH designee, and (iii) a third designee with relevant expertise who is chosen by the other two (in the case of an individual disagreement, the first member may be chosen by the individual awardee). The Arbitration Panel will help resolve both scientific and programmatic issues that develop during the course of work and that restrict progress. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with NIH regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16.

2.A.5. Yearly Milestones

Each Awardee will be asked to define a set of yearly milestones at the time of the award and to update these milestones annually at the anniversary date. These will be made a condition of the award. In accord with the procedures described above, NIH may withhold or reduce funds for a project that substantially fails to meet its milestones or to maintain the state of the art. Further, an awardee that substantially surpasses acknowledged goals in production and quality may be eligible for additional competitive or non-competitive supplemental funds to support the construction of additional driver lines. This would be subject to perceived demand from the Neuroscience Blueprint Institutes and Centers as well as being contingent on the availability of appropriate funds.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (https://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement. Awardees will be required to submit periodic (at least every six months) progress reports in a standard format, as agreed upon by the Steering Committee.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

Sharing Research Data:Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (https://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see https://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement https://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

NIH Public Access Policy:NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

URLs in NIH Grant Applications or Appendices:All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at https://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.